1. Field of the Invention
The present invention concerns nano-scale power cells and power cell aggregates (bio-nano power cells or BNPC) that derive power from compounds found in biological systems and methods of their manufacture and use. Bio-nano power cells include bio-nano sensors, bio-nano fuel cells, bio-nano batteries, biosensors, biofuel cells and biobatteries. More particularly, the present invention relates to the preparation of bio-nano power cells that are biocompatible and capable of producing flash, intermittent, or continuous power by electrolyzing compounds found in biological systems and methods of their manufacture and use.
2. Description of Related Art
Producing flash, intermittent, or continuous electrical power from energy sources available in biological systems has long been desired. As availability of traditional energy systems diminish, compounds and systems that efficiently convert energy rich compounds found in biological systems offer seemingly unlimited potential for energy production. Also, compounds and systems that efficiently generate electrical power in situ are needed to power smaller, integrated medical devices and to power on-demand, targeted delivery of pharmaceuticals. These compounds and systems, while highly desired, have been difficult to prepare and implement for a variety of reasons.
Various systems to meet this need have been attempted. Those that are useful as a component of this invention are discussed below.
Enzyme Based Redox Mediators
Electrochemical sensors, based on enzyme mediators, are widely used in the detection of analytes in agricultural and biotechnological, clinical, and environmental applications. The electro-oxidation or electro-reduction of the enzyme is often facilitated by the presence of a redox mediator that assists in the electrical communication between the working electrode and the enzyme. When the substrate of the enzyme is electro-oxidized, the redox mediator transports electrons from the substrate-reduced enzyme to the electrode; when the substrate is electro-reduced, the redox mediator transports electrons from the electrode to the substrate-oxidized enzyme.
Transition metal complexes, developed by Michael Grätzel (e.g., described in U.S. Pat. Nos. 5,378,628; 5,393,903, the disclosures of which are hereby incorporated by reference) and developed by Adam Heller (e.g., described in U.S. Pat. Nos. 5,965,380; 6,162,611; 6,329,161; 6,514,718; 6,605,200; 6,605,201; 6,676,816; 6,881,551; and 7,090,756, and US Published Patent Applications 20030096997; 20040040840; 20040099529; 20060149067; 20070007132; and 20090099434, the disclosures of which are hereby incorporated by reference) can be used as redox mediators in enzyme based electrochemical sensors. The following formula depicts these entities.

The metal (M) in Formula A can be various metals, including iron, cobalt, ruthenium, osmium or vanadium. The ligands (L1′, L2′, L3′, L4′, L5′, L6′) can be various chelants, including monomeric, cyclic, bidentate, or polymeric entities which form a chelate with (M). c is an integer selected from −1 to −5, 0 or +1 to +5 indicating a negative, neutral or positive charge. X represents a counter ion and d is an integer from 1 to 5 representing the number of counter ions. Formula A is charge neutral. These biosensor can be functionalized by coupling targeting moieties, such as glucose oxidase, lactate oxidase, and other moieties to form amperometric biosensors for the measurement of glucose, lactate and other analytes, respectively.
Redox centers, for example Os2+/3+, can be coordinated with five heterocyclic nitrogens and an additional ligand such as, for example, a chloride anion. An example of such a coordination complex includes: two bipyridine ligands which form stable coordinative bonds; the pyridine of poly(4-vinylpyridine) which forms a weaker coordinative bond; or a chloride anion which forms the least stable coordinative bond.
Alternatively, redox centers, such as Os2+/3+, can be coordinated with six heterocyclic nitrogen atoms in its inner coordination sphere. The six coordinating atoms are preferably paired in the ligands; for example, each ligand is composed of at least two rings. Pairing of the coordinating atoms can influence the potential of an electrode used in conjunction with redox polymers.
Metal complexes with charged linkers for use as luminescent marker groups in an immunoassay are described in U.S. Pat. Nos. 5,958,783 and 5,981,286, illustrating the use of metal ions with ligands that have reactive or activatable functional groups.
Transition Metal Complex Polymers [TMC Polymers]
Transition metal complexes can be directly or indirectly attached to a polymeric backbone, depending on the availability and nature of the reactive groups on the complex and the polymeric backbone. For example, the pyridine groups in poly(4-vinylpyridine) or the imidazole groups in poly(N-vinylimidazole) are capable of acting as monodentate ligands and thus can be attached to a metal center (M) directly. Alternatively, the pyridine groups in poly(4-vinylpyridine) or the imidazole groups in poly(N-vinylimidazole) can be quaternized with a substituted alkyl moiety having a suitable reactive group, such as a carboxylate function, that can be activated to form a covalent bond with a reactive group, such as an amine, of the transition metal complex. Use of these TMC to analyze various analytes has been tried.
Voltages
Typically, for analysis of glucose, the potential at which the working electrode, coated with the redox polymer, is poised negative at about ±250 mV vs. SCE (standard calomel electrode). Preferably, the electrode is poised negative at about +150 mV vs. SCE. Poising the electrode at these potentials reduces the interfering electro-oxidation of constituents of biological solutions (such as, for example, urate, ascorbate and acetaminophen). The potential can be modified by altering the ligand structure of the complex of Formula A.
The redox potential of a redox polymer, as described herein, is related to the potential at which the electrode is poised. Selection of a redox polymer with a desired redox potential allows tuning of the potential at which the electrode is best poised. The redox potentials of a number of the redox polymers described herein are negative at about +150 mV vs. SCE and can be negative at about +50 mV vs. SCE to allow the poising of the electrode potentials negative at about +250 mV vs. SCE and preferably negative at about +150 mV vs. SCE.
The strength of the coordination bond can influence the potential of the redox centers in the redox polymers. Typically, the stronger the coordinative bond, the more positive the redox potential. A shift in the potential of a redox center resulting from a change in the coordination sphere of the transition metal can produce a labile transition metal complex. For example, when the redox potential of an Os2+/3+ complex is downshifted by changing the coordination sphere, the complex becomes labile. Such a labile transition metal complex may be undesirable when fashioning a metal complex polymer for use as a redox mediator and can be avoided through the use of weakly coordinating multidentate or chelating heterocyclics as ligands.
Voltages that different transition metal complexes (TMC) can generate are discussed in various patents (for example U.S. Pat. Nos. 6,605,200; 6,605,201; 6,676,816; 6,881,551; 7,090,756, and US Published Patent Applications 20030096997; 20040040840; 20040099529; 20060149067; 20070007132; and 20090099434, the disclosures of which are hereby incorporated by reference).
Some examples of TMC of Formula A are shown below:
Biosensors
An example of the components of a functionalized transition metal complex (TMC) is shown below.

It is the reaction product of osmium hexachloride, bipyridine, polyimidazole, and polyethylene glycol diglycidyl ether. Either glucose oxidase (GOX) or lactate oxidase (LOX) can be added to create a biosensor complex for the measurement of glucose or lactate, respectively. An example of such biosensors is shown in FIG. 1. TMC Polymers, discussed above, improve electron transport; when used the biosensors are called “wired enzyme” biosensors. These polymers can be used for biosensors as described as examples in U.S. Pat. Nos. 5,965,380; 6,162,611; 6,329,161; 6,514,718; 6,881,551 and 7,190,988.
Biofuel Cells
Transition metal complexes described above in Formula A can also be used for the preparation of biological fuel cells (e.g., U.S. Pat. Nos. 6,294,281; 6,531,239; 7,018,735; 7,238,442 and US Published Patent Applications 20070248850 and 20080044721). The use of anode enzymes (e.g., oxidase or dehydrogenase), use of cathode enzymes (e.g., laccase, ascorbate oxidase, creuloplamine or bilirubin oxidase) are also discussed.
Issues of Biosensors
While the biosensors described by Adam Heller, et al. in the patents listed above generate good voltages, the practical utility of these compounds is restricted because of bio-fouling. Generally, a separate membrane layer or other layer is needed to have adequate biocompatibility for use (see FIG. 1) and this greatly reduces the utility of these transition metal complexes.
Clearly, it would be advantageous to increase the biocompatibility of such a system.
Dendritic Polymers
A wide range of dendritic polymers have been disclosed (see Dendrimers and Other Dendritic Polymers, eds. J. M. J. Fréchet, D. A. Tomalia, pub. John Wiley and Sons, 2001). Among the possible dendritic polymers are dendrimers such as PAMAM dendrimers [poly(amidoamine)], PEI dendrimers [poly(ethyleneimine)], PEHAM dendrimers [poly(etherhydroxylamine)]. Also included as dendritic polymers are dendrons, dendrigrafts, tectodendrimers, comb-branched polyethers and others known as dendritic polymers such as polylysine and hyperbranched polyethers.
Other dendritic polymers are hyper-branched polymers, developed by Donald A. Tomalia and others, where a core is surrounded with branching atoms that provide unique solubility, biocompatibility, and/or structural properties. These polymers do not have the complete regularity of the dendrimers but are useful in many applications.
Nano-scale technologies offer considerable promise to create power cells with the necessary biocompatibility for nano-scale molecules and larger polymeric compounds without requiring secondary fabrication steps. Recent advances, by Tomalia, et al. in US Published Patent Application 20070298006 (which disclosure is hereby incorporated by reference), illustrate how dendritic polymers can add biocompatible groups to the surface of nano-scale molecules and polymeric compounds. (See FIG. 2 for a depiction of these dendrimers.) Particularly described are the PEHAM dendrimers. Also discussed are ring-opening reactions to prepare branched polymer systems, explanations of how steric effects impact design of synthetic compounds at the nanoscale level, (i.e. 1-100 nm) and inherent difficulties in the synthesis of dendrimers.
Dendritic bipyridines with reactive sites have been synthesized by Issberger and Vogtle, et al. and used to make ruthenium chelates. [See Jörg Issberger, Fritz Vogtle, Luisa DeCola, Vincenzo Balzani, Chem Eur., J., 1997, 3 (5).]
Dendritic materials for enhanced performance of energy storage devices have been prepared by Newkome and Moorefield in U.S. Pat. No. 6,399,717 and Newkome in U.S. Pat. No. 7,250,534. These patents illustrate the use of dendritic building blocks to create metallo-based (macro) molecules for magneto resistive disk drive heads.
Dendritic Polymers with Carried Materials
These dendritic polymers can be used for a wide variety of applications, including those that require useful materials to be carried within the interstitial spaces of the dendritic polymer and/or on its surface for many uses, including but not limited to, for chemotherapies, controlled release, carried material delivery, drug releasing devices, polyvalent pharmaceutical moieties, targeted therapies, diagnostics, and therapeutics. Among those carried materials that offer great utility are agricultural materials, antibodies, antibody fragments, aptamers, bioactive agents, biological response modifiers, diagnostic opacifiers, fluorescent moieties, pharmaceuticals, scavenging agents, agricultural materials, hormones, immune-potentiating agents, pesticides, bioactive agents, signal absorbers, signal generators, metal ions, pesticides, pharmaceuticals, radionuclides, scavenging insecticides, bioactive agents, toxins, and many other materials. Any material can be carried within the dendritic polymer so long as it does not appreciably disturb the physical structure of the polymer and is compatible with it. The material may be encapsulated or surface attached as explained in US Published Patent Application 20070298006. When these materials are present with a dendrimer then it is termed a conjugate. Thus FIG. 2A with a carried material is a dendrimer conjugate; FIG. 2B with a carried material is a dendrimer dimer aggregate conjugate.
The surface groups can be modified to have a targeting receptor moiety present and solubilizer groups to aid in the delivery of the carried material.
Issues with Dendritic Polymers
While dendritic polymers offer significant potential, delivery of carried material is not “on-demand” but rather involves changes in pH or slow diffusion to release the carried material at the desired site.
Clearly, it would be advantageous to have a system that could meet the needs for on-demand delivery of carried materials.